Ehrlichioses are emerging life-threatening diseases transmitted by ticks in humans and animals worldwide. Although mechanisms of systemic immunity and immunopathogenesis to needle inoculated disseminated ehrlichiosis have been characterized, the early events in the cutaneous tick transmission site and draining lymph nodes have not been investigated. The role of the vector in pathogen transmission and modulation of the host response requires an animal model of tick transmission to determine the mechanisms of establishment of infection. Under some condition tick saliva causes an imbalance of cytokine regulation, and also suppresses host innate and adaptive immunity by inhibiting antigen presentation, effector cell migration, and microbicidal mechanisms. These disturbances of the host response create an environment for pathogens to establish infection. The long term goal of this project is to determine the role of the vector-host-pathogen interactions on the establishment of ehrlichial infection and the mechanisms of ehrlichial evasion of host defenses. The objective of this application is to characterize a tick transmission model and identify the early events of the immune response to the tick-transmitted ehrlichiae. Our central hypothesis is that tick saliva modulates the local host immune response facilitating establishment of ehrlichial infection. To test our hypothesis we will: (1) Characterize vector transmission of monocytotropic ehrlichiosis. Working hypothesis: The life cycle of ehrlichiae within the vector is initiated in th midgut followed by ehrlichial migration to the salivary glands, where the bacteria replicate during transmission; and (2) characterize the primary immune response to ehrlichial infection transmitted by tick feeding compared to needle inoculation. Working hypothesis: Establishment of ehrlichial infection is favored by modulation of innate immunity by tick saliva leading to ehrlichial entry into APCs (DCs and macrophages) and dissemination by evading the host defenses. We expect to understand the earliest events in the host immune response (innate immunity) and disease establishment in monocytotropic ehrlichiosis, as well as the host-vector-pathogen interface.